Lysostaphin is a 27-kDa protein produced by Staphylococcus simulans biovar staphyloliticus. The protein is a potent endopeptidase that cleaves pentaglycine linkages associated with the bacterial cell wall of nearly all known staphylococcal species (although it is inactive against all other bacterial genera). Thus, upon secretion by S. simulans, lysostaphin kills staphylococcal species that may compete with S. simulans for nutrients.
In view of its activity against many staphylococcal species (including S. aureus), lysostaphin has been tested for possible antibacterial activity in animal models. See Schuhardt et al. (1964) J. Bacteriol 88:815-816. Parenteral administration of lysostaphin analogs to treat patients suffering from staphylococcal infections has been described. See U.S. Patent Application Publication No. 2002/0006406.
Because of its relatively short half-file, however, the recommended frequency for dosing lysostaphin analogs can be as often as three times a day. See U.S. Patent Application Publication No. 2002/0006406. Lysostaphin itself is also expected to require relatively frequent injections. Moreover, because lysostaphin is a foreign protein, administration of lysostaphin likely will result in the precipitation of an immune response in humans.
Some have suggested the use of PEGylation technology, or the attachment of a poly(ethylene glycol) derivative to a protein, in order to prolong the antimicrobial agent's in vivo half-life. For example, U.S. Patent Application Publication No. 2003/0215436 describes certain poly(ethylene glycol)-lysostaphin conjugates. The described poly(ethylene glycol) reagents result in specific conjugates having specific structures.
Notwithstanding these described conjugates, however, it remains advantageous to provide conjugates of lysostaphin and other antimicrobials that satisfy one or more of the following: conjugates formed from different polymeric reagents (e.g., PEGs having different structures, reactive groups, and so forth); conjugates formed from PEG derivatives having different weight average molecular weights; and conjugates formed from a variety of antimicrobial agents.
Thus, there remains a need in the art to provide additional conjugates of water-soluble polymers and antimicrobial agents. Among other things, one or more embodiments of the present invention is therefore directed to such conjugates as well as to compositions comprising the conjugates and related methods as described herein, which are believed to be new and completely unsuggested by the art.